SUMMARY Glucose homeostasis and food intake are both regulated by gut hormones secreted from enteroendocrine L- cells in the lower gut following stimulation by nutrients. This process is impaired in diabetes but is restored with delivery of dietary nutrients such as amino acids and fatty acids to the lower gut, such as after gastric bypass surgery and during fermentation of carbohydrates in the colon, both of which resolve diabetes. While these approaches to deliver nutrients to the lower gut have complications, their efficacy and durability of effect is superior to existing drugs. BioKier has identified a simple, direct, and safe method to deliver one of the key nutrients to the colon to treat diabetes and other conditions characterized by impaired L-cell stimulation. BioKier's concept involves delivering a nutrient that is a gut hormone secretagogue to the colon via a colon- targeting formulation that bypasses the absorptive upper gut. BioKier's single-dose studies have shown that direct delivery of specific nutrients via catheter to the colon of diabetic animals and humans restored the oral glucose-induced gut hormone response. Also, chronic treatment with an oral formulation of butyrate completely prevented the development of diabetes in the industry standard ZDF rat model, providing preclinical proof of concept. Furthermore, oral, sustained-release, colon targeted L-glutamine had significant effects on insulin sensitivity, when dosed for 4 weeks in T2D patients (Phase II of the Fast-Track). While a single dose of L- glutamine resulted in stimulation of L-cells and GLP-1, no effect was seen on GLP-1 section at end of a 4-week BID treatment in T2D patients. Repeated delivery of L-glutamine to the colon resulted in increased utilization of L-glutamine by colonic bacteria. On the contrary, the effects of butyrate, also shown to stimulate GLP-1 secretion in BioKier's preclinical and clinical studies, are sustained long-term. In addition to the effects of colon-targeted butyrate tablets in the rat model, BioKier has confirmatory human data with colonic fermentation-derived butyrate. Although very effective, the fermentation approach to generating butyrate in the colon is not suitable for widespread utilization due to the severe GI side effects of fermentation. To build on the validation of the formulation in Phase II and the known long-term effects of butyrate, we are focusing this Phase IIB application on colon-targeted butyrate in an oral tablet. To conduct human testing, BioKier's colonic butyrate formulation, BKR-017, will be manufactured, validated and stability tested for clinical development (Aim 1). Aim 2 involves conduct of a Phase 2a clinical trial to evaluate insulin sensitivity, plasma GLP-1 and insulin responses, and safety of BKR-017 in T2D patients to indirectly compare to results obtained with BKR-013 (L-glutamine). Aim 3, a larger dose-ranging study will determine an effective dose for commercial use. Progress thus far has attracted the interest of several nutritional and pharmaceutical partners who have indicated the results of the clinical study to be funded by this application are crucial to discussions of a commercial agreement to bring the product to market.